Autoinflammatory diseases (AIDs) and autoimmune diseases (ADs) are characterized by an aberrant chronic activation of the immune system which causes tissue inflammation and damage in genetically predisposed individuals. Pathogenetic mechanisms underlying this damage differ between these two types of diseases; in AIDs, the innate immune system is directly responsible for tissue inflammation, while in ADs it works by activating the adaptive immune system, which becomes the main effector of the inflammatory process. Despite the fact that AIDs have only been recently defined, they are older than ADs. The innate immune system is found in plants and animals, and it developed earlier than the adaptive immune system, which first appeared in jawed vertebrates. According to genetic background and clinical, serological, and radiological findings, AIDs and ADs might be considered as a single spectrum of disorders, with a wide range of manifestations. Indeed, autoinflammatory-like diseases have been reported in simple organisms such as Drosophila melanogaster and Caenorhabditis elegans. We analyzed here the main pathogenetic and clinical features of these two groups of diseases mostly dealing with their similarities and differences.